Certain pyrrol derivatives are known to be important intermediates in the synthesis of bioactive porphyrins such as octaethylporphyrin. For example, pyrrol derivatives, compounds A-C, and the dipyrromethanes D and E have been utilized as intermediates in the synthesis of octaethylporphyrin (compound F where R.sup.1 =R.sup.2 =Et) and for the preparation of certain fluorosubstituted porphyrins (e.g. compound G where R.sup.1 =R.sup.2 =Et, R=C.sub.6 H.sub.4 --CF.sub.3). The former is widely used for biological modeling studies and the latter porphyrins are potential agents for the treatment and diagnosis of cancers. Pyrrol derivatives are also important intermediates for synthesizing biopigments, drugs and agrochemicals. ##STR1##
Previously reported synthetic methodologies for pyrrol derivatives are often tedious, and typically provide relatively low yields. For example, 3,4-diethylpyrrol (compound B where R.sup.1 =R.sup.2 =Et), has been prepared in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), tetrahydrofuran (THF), and isopropylalcohol (IPA) in a relatively low yield (38.1-40%), Meyers, A. I., ED., 70 Organic Synthesis, 67-77 (1991). (Scheme 1) ##STR2##
Tetrasubstituted dipyrromethanes are precursors for important types of sterically blocked meso-diarylporphyrins. Several have been prepared using lengthy procedures which provide low yields. (See e.g. Gunter, M. J. et al., J. Org. Chem., 46:4792 (1981); Young, R. et al., J. Am. Chem. Soc., 107:898 (1985)). For example, compound E (3,4,3',4'-tetramethyldipyrromethane) is a precursor meso-diphenylporphyrin. Compound E has been prepared using involved methodologies which provide low yields (8-12%). (See e.g. Scheme 2.) Gunter et al., J. Org. Chem., 46:4792 (1981); Young et al., J. Am. Chem. Soc., 107:898 (1985). ##STR3##
The Gunter et al., supra., and the Young et al., supra, method for the preparation of 3,3',4,4'-tetramethyldipyrromethane, and 3,3'-diethyl-4,4'-dimethyldipyrromethane involved the lengthy Knorr approach (ten or more steps) and gave a very low yield (.ltoreq.10%). In particular, the decarboxylation of compound H with sodium hydroxide proceeds in very low yields owing to its decomposition at the elevated temperatures need for decarboxylation (over 100.degree. C.). A more recent revised procedure is also lengthy and of low yield (about 22%). See Scheme 3. Semeikin, A. S. et al., Izv. Vyss. Uchelon. Zared Khim. Tekhnol., 31:39 (1988). ##STR4##
Irrespective of the route to the final product dipyrrol in Scheme 3, a frequent intermediate contains an ester group (--CO.sub.2 R group) at the alpha or 2 position. Removal of this ester group to form the de-esterified derivative has traditionally been problematic. Typically, an initial step for this process involves the common organic transformation of cleavage of the ester group to form a carboxylic acid by an acidic or basic hydrolysis. However, because pyrrol and dipyrromethane compounds are sensitive to acidic conditions, a more cumbersome procedure has been used to remove the alpha ester group of these compounds through the use of saponification and subsequent thermal decarboxylation. While this method provides a means of preparing 3,4-dialkylpyrrols such as compound B from an esterified compound such as compound A, the yield is very low (38-40%) and the product is not pure, thus requiring purification by vacuum distillation. (Scheme 1.) Meyers, A. I., supra at 68.
The synthesis of porphyrins from pyrrol and dipyrromethane compounds, while well-known, has been of limited utility due to limited availability of pyrrol and dipyrromethane starting compounds. Most of the methods for the synthesis of octaethylporphyrin (OEP) start from 2-ethoxycarbonyl-3,4-diethyl-5-methylpyrrol, which was prepared by the Knorr reaction of ethyl propionylacetate with 2,4-pentanedione. Pain, III, J. B., et al., J. Org. Chem., 44:3857 (1976). (Scheme 2.) This method is inconvenient because of difficulties in preparing the starting materials and in transforming the 5-methyl group of the pyrrol ring system. Although new methods have been designed prior to the techniques disclosed herein, the preparation of OEP has remained troublesome, particularly whenever more than a few grams are required. This is so because of the accompanying formation of by-product I which lowers the yield of the desired pyrrol compound A, and allows it to be isolated only on a small scale by a difficult chromatography procedure. Ono, N., et al., Tetrahedron, 46:7843 (1990).
Oxazoles (compound J) are intermediates to pharmaceutically interesting C-acyl-.alpha.-amino acids (compound K) which, in turn, are useful intermediates in the synthesis of .beta.-hydroxyamino acids, especially .beta.-aryl serines and amino alcohols including sympathomimetic agents such as ephedrine and epinephrine. ##STR5## Traditional synthesis of oxazoles through reaction of isocyanoacetates with acyl chlorides or acid anhydrides in the presence of a large excess of 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) or triethyl amine are typically lengthy (about 48 hours). M. Suzuki et al., Syn. Commun., 2:237 (1972); Suzuki et al., J. Org. Chem., 38:3571 (1973). Modifying the traditional method of oxazole synthesis by reacting an acyl halide with an isocyanoacetate in tetrahydrofuran (THF) in the presence of only 1 equivalent DBU (Scheme 4), and shortening the reaction time to two hours while stirring at room temperature, produced a mixture with a complicated .sup.1 H NMR spectrum, and a GC which showed that based on the limiting starting reactant only about eight percent of the desired oxazole was formed. ##STR6##